Association of Proximal Tubule Secretion With Hyperkalemia Risk, Treatment Response, and Outcomes in Heart Failure With Preserved Ejection Fraction

Rationale & Objective Endogenous biomarkers reflecting impaired kidney tubular secretion are associated with risk of hyperkalemia in patients with hypertension and chronic kidney disease (CKD). Whether these biomarkers are associated with risk of hyperkalemia, therapeutic response, and adverse cardiovascular and kidney events in heart failure (HF) patients receiving mineralocorticoid receptor antagonists (MRAs) is unknown. Study Design Observational cohort study. Setting & Participants Individuals with HF with preserved ejection fraction (HFpEF) enrolled in the TOPCAT study. Predictors Summary secretion score incorporating urine-to-plasma ratios of 9 secretion markers measured in paired samples at baseline. Outcomes Change in serum potassium during follow-up, measures of treatment response assessed by change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score and NT-proBNP over 12 months, and adverse cardiovascular and kidney events. Analytic Approach Linear mixed-effects models, Cox proportional hazards models, and linear regression adjusting for risk factors, estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR). Results Among 372 TOPCAT participants, 179 (48%) were randomized to spironolactone, 45% were women, the mean age was 70 ± 10 years and eGFR was 66 ± 18 ml/min/1.73 m 2 . In adjusted models, higher secretion score was not associated with changes in serum potassium, change in KCCQ ≥5 points, change in NT-proBNP, adverse cardiovascular or kidney events. In adjusted models, higher secretion score was associated with lower KCCQ at 12 months (change -3.5, 95% CI -6.6 to -0.4) in the spironolactone arm, but not in the placebo arm. Limitations Low number of events, confounding from Eastern Europe participants who may have not had HFpEF or taken prescribed therapies. Conclusions Biomarkers of tubular secretion are not associated with risk of hyperkalemia, treatment response, or cardiovascular and kidney events in individuals with HFpEF.